Journal of Gastroenterology

, Volume 42, Issue 12, pp 947–956 | Cite as

The production of interferon-γ-inducible protein 10 by granulocytes and monocytes is associated with ulcerative colitis disease activity

  • Atsushi Noguchi
  • Kenji Watanabe
  • Shosaku Narumi
  • Hirokazu Yamagami
  • Yasuhiro Fujiwara
  • Kazuhide Higuchi
  • Nobuhide Oshitani
  • Tetsuo Arakawa
Alimentary Tract



To clarify which types of cells produce interferon-γ-inducible protein 10 (IP-10) and whether IP-10 is associated with the development of ulcerative colitis (UC), we investigated IP-10 production in UC patients.


Serum IP-10 levels were measured using enzyme-linked immunosorbent assay in 29 patients with active and 21 with inactive UC and in 20 controls. The production of IP-10 by granulocytes and monocytes adsorbed to G-1 beads was examined. In 21 active UC patients treated with granulocyte and monocyte/macrophage adsorptive apheresis (GMA), serum IP-10 levels were measured before and after treatment. IP-10-positive cells in UC mucosa were also examined immunohistochemically using tissues obtained by surgical resection and colonoscopic biopsies.


Serum IP-10 levels in active UC patients were significantly higher than those in inactive patients, although even in the latter the levels were increased compared with those in controls. IP-10 production by granulocytes and monocytes in active UC patients was significantly higher than that in controls. Furthermore, the number of IP-10-positive cells was elevated in the colonic mucosa of patients with active UC, and one of the main subpopulations of IP-10-positive cells was granulocytes. Serum IP-10 levels decreased following GMA treatment in responders, but not in nonresponders. Interestingly, serum IP-10 levels before GMA were higher in responders than in nonresponders. In parallel with the serum levels, IP-10-positive cells also decreased following GMA treatment.


Serum IP-10 levels reflected UC disease activity, and the source of IP-10 was granulocytes and monocytes. Furthermore, serum IP-10 levels may be a marker for the responsiveness of patients to GMA treatment.

Key words

ulcerative colitis IP-10 adsorptive apheresis granulocyte monocyte 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Podolsky, DK 2002Inflammatory bowel diseaseN Engl J Med34741729PubMedCrossRefGoogle Scholar
  2. 2.
    Shanahan, F 2001Inflammatory bowel disease: immunodiagnostics, immunotherapeutics, and ecotherapeuticsGastroenterology12062235PubMedCrossRefGoogle Scholar
  3. 3.
    Hanauer, SB 2006Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunitiesInflamm Bowel Dis12S39PubMedCrossRefGoogle Scholar
  4. 4.
    MacDermott, RP, Sanderson, IR, Reinecker, HC 1998The central role of chemokines (chemotactic cytokines) in the immunopathogenesis of ulcerative colitis and Crohn's diseaseInflamm Bowel Dis45467PubMedCrossRefGoogle Scholar
  5. 5.
    Luster, AD 1998Chemokines—chemotactic cytokines that mediate inflammationN Engl J Med33843645PubMedCrossRefGoogle Scholar
  6. 6.
    Dwinell, MB, Lugering, N, Eckmann, L, Kagnoff, MF 2001Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cellsGastroenterology1204959PubMedCrossRefGoogle Scholar
  7. 7.
    Agace, WW, Roberts, AI, Wu, L, Greineder, C, Ebert, EC, Parker, CM 2000Human intestinal lamina propria and intraepithelial lymphocytes express receptors specific for chemokines induced by inflammationEur J Immunol3081926PubMedCrossRefGoogle Scholar
  8. 8.
    Farber, JM 1997Mig and IP-10: CXC chemokines that target lymphocytesJ Leukoc Biol6124657PubMedGoogle Scholar
  9. 9.
    Gasperini, S, Marchi, M, Calzetti, F, Laudanna, C, Vicentini, L, Olsen, H,  et al. 1999Gene expression and production of the monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein-10 (IP-10) chemokines by human neutrophilsJ Immunol162492837PubMedGoogle Scholar
  10. 10.
    Hamilton, NH, Banyer, JL, Hapel, AJ, Mahalingam, S, Ramsay, AJ, Ramshaw, IA,  et al. 2002IFN-gamma regulates murine interferon-inducible T cell alpha chemokine (I-TAC) expression in dendritic cell lines and during experimental autoimmune encephalomyelitis (EAE)Scand J Immunol551717PubMedGoogle Scholar
  11. 11.
    Kolios, G, Wright, KL, Jordan, NJ, Leithead, JB, Robertson, DA, Westwick, J 1999C-X-C and C-C chemokine expression and secretion by the human colonic epithelial cell line, HT-29: differential effect of T lymphocyte-derived cytokinesEur J Immunol295306PubMedCrossRefGoogle Scholar
  12. 12.
    Sauty, A, Dziejman, M, Taha, RA, Iarossi, AS, Neote, K, Garcia-Zepeda, EA,  et al. 1999The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cellsJ Immunol162354958PubMedGoogle Scholar
  13. 13.
    Narumi, S, Tominaga, Y, Tamaru, M, Shimai, S, Okumura, H, Nishioji, K,  et al. 1997Expression of IFN-inducible protein-10 in chronic hepatitisJ Immunol158553644PubMedGoogle Scholar
  14. 14.
    Shimada, A, Morimoto, J, Kodama, K, Suzuki, R, Oikawa, Y, Funae, O,  et al. 2001Elevated serum IP-10 levels observed in type 1 diabetesDiabetes Care245105PubMedCrossRefGoogle Scholar
  15. 15.
    Sorensen, TL, Tani, M, Jensen, J, Pierce, V, Pierce, V, Lucchinetti, C,  et al. 1999Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patientsJ Clin Invest10380715PubMedGoogle Scholar
  16. 16.
    Uguccioni, M, Gionchetti, P, Robbiani, DF, Rizzello, F, Peruzzo, S, Campieri, M,  et al. 1999Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitisAm J Pathol1553316PubMedGoogle Scholar
  17. 17.
    Helwig, U, Gionchetti, P, Rizzello, F, Lammers, K, Kuhbacher, T, Schreiber, S,  et al. 2004CXC and CC chemokine expression in inflamed and noninflamed pelvic ileal pouch tissueInt J Colorectal Dis1916570PubMedCrossRefGoogle Scholar
  18. 18.
    Autschbach, F, Giese, T, Gassler, N, Sido, B, Heuschen, G, Heuschen, U,  et al. 2002Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn's diseaseVirchows Arch44150013PubMedCrossRefGoogle Scholar
  19. 19.
    Sasaki, S, Yoneyama, H, Suzuki, K, Suriki, H, Aiba, T, Watanabe, S,  et al. 2002Blockade of CXCL10 protects mice from acute colitis and enhances crypt cell survivalEur J Immunol323197205PubMedCrossRefGoogle Scholar
  20. 20.
    Shimoyama, T, Sawada, K, Hiwatashi, N, Sawada, T, Matsueda, K, Munakata, A,  et al. 2001Safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active ulcerative colitis: a multicenter studyJ Clin Apher1619PubMedCrossRefGoogle Scholar
  21. 21.
    Hanai, H, Watanabe, F, Takeuchi, K, Iida, T, Yamada, M, Iwaoka, Y,  et al. 2003Leukocyte adsorptive apheresis for the treatment of active ulcerative colitis: a prospective, uncontrolled, pilot studyClin Gastroenterol Hepatol12835PubMedCrossRefGoogle Scholar
  22. 22.
    Suzuki, Y, Yoshimura, N, Saniabadi, AR, Saito, Y 2004Selective granulocyte and monocyte adsorptive apheresis as a first-line treatment for steroid naive patients with active ulcerative colitis: a prospective uncontrolled studyDig Dis Sci4956571PubMedCrossRefGoogle Scholar
  23. 23.
    Naganuma, M, Funakoshi, S, Sakuraba, A, Takagi, H, Inoue, N, Ogata, H,  et al. 2004Granulocytapheresis is useful as an alternative therapy in patients with steroid-refractory or -dependent ulcerative colitisInflamm Bowel Dis102517PubMedCrossRefGoogle Scholar
  24. 24.
    Hanai, H, Watanabe, F, Yamada, M, Sato, Y, Takeuchi, K, Iida, T,  et al. 2004Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitisDigestion703644PubMedCrossRefGoogle Scholar
  25. 25.
    Yamamoto, T, Umegae, S, Kitagawa, T, Yasuda, Y, Yamada, Y, Takahashi, D,  et al. 2004Granulocyte and monocyte adsorptive apheresis in the treatment of active distal ulcerative colitis: a prospective, pilot studyAliment Pharmacol Ther2078392PubMedCrossRefGoogle Scholar
  26. 26.
    Domenech, E, Hinojosa, J, Esteve-Comas, M, Gomollon, F, Herrera, JM, Bastida, G,  et al. 2004Granulocyteaphaeresis in steroid-dependent inflammatory bowel disease: a prospective, open, pilot studyAliment Pharmacol Ther20134752PubMedCrossRefGoogle Scholar
  27. 27.
    Giampaolo, B, Giuseppe, P, Michele, B, Alessandro, M, Fabrizio, S, Alfonso, C 2006Treatment of active steroid-refractory inflammatory bowel diseases with granulocytapheresis: Our experience with a prospective studyWorld J Gastroenterol1222014PubMedGoogle Scholar
  28. 28.
    Tomomasa, T, Kobayashi, A, Kaneko, H, Mika, S, Maisawa, S, Chino, Y,  et al. 2003Granulocyte adsorptive apheresis for pediatric patients with ulcerative colitisDig Dis Sci487504PubMedCrossRefGoogle Scholar
  29. 29.
    Pineda, AA 2006Developments in the apheresis procedure for the treatment of inflammatory bowel diseaseInflamm Bowel Dis12S104PubMedCrossRefGoogle Scholar
  30. 30.
    Sandborn, WJ 2006Preliminary data on the use of apheresis in inflammatory bowel diseaseInflamm Bowel Dis12S1521PubMedCrossRefGoogle Scholar
  31. 31.
    Saniabadi, AR, Hanai, H, Takeuchi, K, Umemura, K, Nakashima, M, Adachi, T,  et al. 2003Adacolumn, an adsorptive carrier based granulocyte and monocyte apheresis device for the treatment of inflammatory and refractory diseases associated with leukocytesTher Apher Dial74859PubMedCrossRefGoogle Scholar
  32. 32.
    Ohara, M, Saniabadi, AR, Kokuma, S, Hirata, I, Adachi, M, Agishi, T,  et al. 1997Granulocytapheresis in the treatment of patients with rheumatoid arthritisArtif Organs2198994PubMedCrossRefGoogle Scholar
  33. 33.
    Saniabadi, AR, Hanai, H, Suzuki, Y, Ohmori, T, Sawada, K, Yoshimura, N,  et al. 2005Adacolumn for selective leukocytapheresis as a non-pharmacological treatment for patients with disorders of the immune system: an adjunct or an alternative to drug therapy?J Clin Apher2017184PubMedCrossRefGoogle Scholar
  34. 34.
    Kashiwagi, N, Sugimura, K, Koiwai, H, Yamamoto, H, Yoshikawa, T, Saniabadi, AR,  et al. 2002Immunomodulatory effects of granulocyte and monocyte adsorption apheresis as a treatment for patients with ulcerative colitisDig Dis Sci47133441PubMedCrossRefGoogle Scholar
  35. 35.
    Ramlow, W, Emmrich, J, Ahrenholz, P, Sparmann, G, Kashiwagi, N, Franz, M,  et al. 2005In vitro and in vivo evaluation of Adacolumn cytapheresis in healthy subjectsJ Clin Apher207280PubMedCrossRefGoogle Scholar
  36. 36.
    Kashiwagi, N, Hirata, I, Kasukawa, R 1998A role for granulocyte and monocyte apheresis in the treatment of rheumatoid arthritisTher Apher213441PubMedCrossRefGoogle Scholar
  37. 37.
    Hanai, H, Watanabe, F, Saniabadi, AR, Matsushitai, I, Takeuchi, K, Iida, T 2002Therapeutic efficacy of granulocyte and monocyte adsorption apheresis in severe active ulcerative colitisDig Dis Sci47234953PubMedCrossRefGoogle Scholar
  38. 38.
    Hanai, H, Iida, T, Yamada, M, Sato, Y, Takeuchi, K, Tanaka, T,  et al. 2006Effects of Adacolumn selective leukocytapheresis on plasma cytokines during active disease in patients with active ulcerative colitisWorld J Gastroenterol1233939PubMedGoogle Scholar
  39. 39.
    Andoh, A, Tsujikawa, T, Inatomi, O, Deguchi, Y, Sasaki, M, Obata, H,  et al. 2005Leukocytapheresis therapy modulates circulating T cell subsets in patients with ulcerative colitisTher Apher Dial92706PubMedCrossRefGoogle Scholar
  40. 40.
    Tsukada, Y, Nakamura, T, Iimura, M, Iizuka, BE, Hayashi, N 2002Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresisAm J Gastroenterol9728208PubMedCrossRefGoogle Scholar
  41. 41.
    Schroeder, KW, Tremaine, WJ, Ilstrup, DM 1987Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized studyN Engl J Med31716259PubMedCrossRefGoogle Scholar
  42. 42.
    Majumder, S, Zhou, LZ, Chaturvedi, P, Babcock, G, Aras, S, Ransohoff, RM 1998p48/STAT-1 alpha-containing complexes play a predominant role in induction of IFN-gamma-inducible protein, 10 kDa (IP-10) by IFN-gamma alone or in synergy with TNF-alphaJ Immunol161473644PubMedGoogle Scholar
  43. 43.
    Swaak, AJ, van den Brink, HG, Aarden, LA 1996Cytokine production (IL-6 and TNF alpha) in whole blood cell cultures of patients with systemic lupus erythematosusScand J Rheumatol252338PubMedCrossRefGoogle Scholar
  44. 44.
    Kopydlowski, KM, Salkowski, CA, Cody, MJ, van Rooijen, N, Major, J, Hamilton, TA,  et al. 1999Regulation of macrophage chemokine expression by lipopolysaccharidesss in vitro and in vivoJ Immunol163153744PubMedGoogle Scholar
  45. 45.
    Kawai, T, Takeuchi, O, Fujita, T, Inoue, J, Muhlradt, PF, Sato, S,  et al. 2001Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genesJ Immunol167588794PubMedGoogle Scholar
  46. 46.
    Inatomi, O, Andoh, A, Kitamura, K, Yasui, H, Zhang, Z, Fujiyama, Y 2005Butyrate blocks interferon-gamma-inducible protein-10 release in human intestinal subepithelial myofibroblastsJ Gastroenterol404839PubMedCrossRefGoogle Scholar
  47. 47.
    Papadakis, KA, Prehn, J, Zhu, D, Landers, C, Gaiennie, J, Fleshner, PR,  et al. 2004Expression and regulation of the chemokine receptor CXCR3 on lymphocytes from normal and inflammatory bowel disease mucosaInflamm Bowel Dis1077888PubMedCrossRefGoogle Scholar
  48. 48.
    Yuan, YH, ten Hove, T, The, FO, Slors, JF, van Deventer, SJ, te Velde, AA 2001Chemokine receptor CXCR3 expression in inflammatory bowel diseaseInflamm Bowel Dis72816PubMedCrossRefGoogle Scholar
  49. 49.
    Biswas, P, Mantelli, B, Hasson, H, Vecchi, A, Saniabadi, A, Lazzarin, A,  et al. 2003In vivo modulation of leukocyte trafficking receptor following therapeutic purging of myeloid cells: implications for treatment of HIV infection and other immune disordersClin Immunol1093558PubMedCrossRefGoogle Scholar
  50. 50.
    Rutgeerts, P, Sandborn, WJ, Feagan, BG, Reinisch, W, Olson, A, Johanns, J,  et al. 2005Infliximab for induction and maintenance therapy for ulcerative colitisN Engl J Med353246276PubMedCrossRefGoogle Scholar
  51. 51.
    Sawa, Y, Oshitani, N, Adachi, K, Higuchi, K, Matsumoto, T, Arakawa, T 2003Comprehensive analysis of intestinal cytokine messenger RNA profile by real-time quantitative polymerase chain reaction in patients with inflammatory bowel diseaseInt J Mol Med111759PubMedGoogle Scholar
  52. 52.
    Gotteland, M, Lopez, M, Munoz, C, Saez, R, Altshiller, H, Llorens, P,  et al. 1999Local and systemic liberation of proinflammatory cytokines in ulcerative colitisDig Dis Sci448305PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  • Atsushi Noguchi
    • 1
  • Kenji Watanabe
    • 1
  • Shosaku Narumi
    • 2
  • Hirokazu Yamagami
    • 1
  • Yasuhiro Fujiwara
    • 1
  • Kazuhide Higuchi
    • 1
  • Nobuhide Oshitani
    • 1
  • Tetsuo Arakawa
    • 1
  1. 1.Department of GastroenterologyOsaka City University Graduate School of MedicineOsakaJapan
  2. 2.Stelic Institute of Regenerative MedicineTokyoJapan

Personalised recommendations